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S44 Table 1Summary of significant medical events, thoracic computed tomography (CT) and pulmonary function tests (PFTs) in ORBCEL-C and placebo groups at 1 year follow upORBCEL-C Placebo Number of patients followed up 20 21 Significant medical events Number of patients with SMEs 6/20 9/21 Total SME events 7 11 Classification Respiratory,thoracic and mediastinal disorders 4 6 Neoplasm - benign, malignant, unspecified 1 0 Infections and infestations 1 1 Cardiac disorders 1 0 Metabolism and nutrition disorders 0 1 Injury, poisoning and procedural complications 0 1 Renal and urinary disorders 0 1 Gastrointestinal disorders 0 1 Thoracic CT Number of CTs available 5 8 Time to CT (Median, IQR) 181 (157–198) 203 (95–233) Evidence of ILD on CT 4 6 PFTs Number of PFTs available 10 8 Time to PFTs (Median, IQR) 184.5 (117.5–292.75) 203.5 (118.25–242.5) FEV1 (Mean, SD) 84.9 (13.6) 80.5 (13.3) FEV1 <80% predicted (n,%) 4/10 (44%) 4/8 (50%) FVC (Mean, SD) 78.4 (13.2) 79.3 (16.5) FVC <80% predicted (n,%) 5/10 (55%) 5/8 (62.5%) FEV1/FVC ratio (Mean, SD, n) 0.88 (0.12) N=8 0.76 (0.05) N=5 FEV1/FVC <0.7 (n,%) 0 (0%) 0 (0%) TLCO (Mean, SD, n) 78.9 (14.8) N=9 61.9 (13.4) N=7 TLCO <80% (n,%) 6/9 (66.7%) 7/7 (100%) ConclusionsOne year follow up supports the safety of ORBCEL-C MSCs in patients with moderate to severe ARDS due to COVID-19. A similar incidence of pulmonary dysfunction is reported in both groups at long term follow up.Please refer to page A?? for declarations of interest related to this .
ABSTRACT
Acute respiratory distress syndrome (ARDS) is a critical illness characterized by a severe hypoxemic respiratory failure, caused by an inflammatory response which results in diffuse lung damage. Despite decades of research, the treatment of ARDS remains supportive. However, in recent years, cell-based therapies have been the subject of intensive ongoing research efforts, showing relevant therapeutic potential in preclinical ARDS models. Among all the different cells that have been identified as suitable candidates for use, mesenchymal stromal cells (MSCs) have been the most attractive candidates and have generated significant interest. MSCs are multipotent adult stem/stromal cells that can modulate the immune response and enhance repair of damaged tissue in multiple in vivo models. Their promising effect seems to be not primarily mediated by MSCs differentiation and engraftment but more by the paracrine release of different soluble mediators and cellular components such as extracellular vesicles (EVs). Preclinical experiments have provided encouraging evidence for the therapeutic potential of MSCs, leading to the launch of several phase I and II clinical trials that have shown safety of MSCs in ARDS, which became very common nowadays due to the Coronavirus disease (COVID-19) pandemic. However, some translational challenges have yet to be solved, such as the reproducibility of cell harvest, storage, reconstitution, and administration of cells/cell-products, before the therapeutic potential of stem cells therapies can be realized. ©2022 The Author(s). Published by MRE Press.
ABSTRACT
Severe viral pneumonia is a significant cause of morbidity and mortality globally, whether due to outbreaks of endemic viruses, periodic viral epidemics, or the rarer but devastating global viral pandemics. While limited anti-viral therapies exist, there is a paucity of direct therapies to directly attenuate viral pneumonia-induced lung injury, and management therefore remains largely supportive. Mesenchymal stromal/stem cells (MSCs) are receiving considerable attention as a cytotherapeutic for viral pneumonia. Several properties of MSCs position them as a promising therapeutic strategy for viral pneumonia-induced lung injury as demonstrated in pre-clinical studies in relevant models. More recently, early phase clinical studies have demonstrated a reassuring safety profile of these cells. These investigations have taken on an added importance and urgency during the COVID-19 pandemic, with multiple trials in progress across the globe. In parallel with clinical translation, strategies are being investigated to enhance the therapeutic potential of these cells in vivo, with different MSC tissue sources, specific cellular products including cell-free options, and strategies to 'licence' or 'pre-activate' these cells, all being explored. This review will assess the therapeutic potential of MSC-based therapies for severe viral pneumonia. It will describe the aetiology and epidemiology of severe viral pneumonia, describe current therapeutic approaches, and examine the data suggesting therapeutic potential of MSCs for severe viral pneumonia in pre-clinical and clinical studies. The challenges and opportunities for MSC-based therapies will then be considered.
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Rationale Heterogeneous respiratory system static compliance (CRS) values and levels of hypoxemia in patients with novel coronavirus disease (COVID-19) requiring mechanical ventilation have been reported in previous smallcase series or studies conducted at a national level.Methods We designed a retrospective observational cohort study with rapid data gathering from the international COVID-19 Critical Care Consortium study to comprehensively describe the impact of CRS on the ventilatory management and outcomes of COVID-19 patients on mechanical ventilation (MV), admitted to intensive care units (ICU) worldwide.Results We enrolled 318 COVID-19 patients enrolled into the study from January 14th through September 31th, 2020 in 19 countries and stratified into two CRS groups. CRS was calculated as: tidal volume/[airway plateau pressure-positive endexpiratory pressure (PEEP)] and available within 48h from commencement of MV in 318 patients. Patients were mean±SD of 58.0±12.2, predominantly from Europe (54%) and males (68%). Median CRS (IQR) was 34.1 mL/cmH2O (26.5-45.5) and PaO2/FiO2 was 119 mmHg (87.1-164) and was not correlated with CRS. Female sex presented lower CRS than in males (95% CI:-13.8 to-8.5 P<0.001) and higher body mass index (34.7±10.9 vs 29.1±6.0, p<0.001). Median (IQR) PEEP was 12 cmH2O (10-15), throughout the range of CRS, while median (IQR) driving pressure was 12.3 (10-15) cmH2O and significantly decreased as CRS improved (p<0.001). No differences were found in comorbidities and clinical management between CRS strata. In addition, 28-day ICU mortality and hospital mortality did not differ between CRSgroups.Conclusions This multicentre report provides a comprehensive account of CRS in COVID-19 patients on MV-predominantly males or overweight females, in their late 50s-admitted to ICU during the first international outbreaks. Phenotypes associated with different CRS upon commencement of MV could not be identified.
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Rationale: Patients with COVID-19 commonly develop severe hypoxemic respiratory failure and require invasive mechanical ventilation (MV). The disease burden and predictors of mortality in this population remain uncertain. Methods: Prospective observational cohort study from 139 intensive care units of the international COVID-19 Critical Care Consortium. Patients enrolled from January 14th through November 31st 2020 were included in the analysis. Patient's characteristics and clinical data were assessed. Multivariable Cox proportional hazards analysis was conducted to identify indipendent predictors of mortality within 28 days from commencement of MV. Results: 1578 patients on MV were included into the analysis. Mean±SD age was 59 years±13 and patients were predominantly males (66%). 542 Patients (34.4%) died within 28 days from commencement of MV. Nonsurvivors were slightly older (mean age±SD 62±13 vs. 59±13) and presented more frequently hypertension, chronic cardiac disease and diabetes. Median (IQR) PaO2/FiO2 upon commencement of MV was 96 (68-135) and 111 (81-173) in patients who did not survive vs. survivors, respectively (p=0.04). ECMO (13% vs 25%, p<0.01), inhaled nitric oxide (11% vs 15%, p=0.02) and recruitment manoeauvres (26% vs 31%, p<0.01) were used less frequently in patients who did not survive. Independent risk factors associated with 28-day mortality included age older than 70 years (hazard ratio [HR], 2.83;95% CI, 1.32-6.07), higher creatinine levels upon ICU admission (HR, 1.20;95% CI, 1.03-1.40), and lower pH within 24h from commencement of MV (HR, 0.12;95% CI, 0.02-0.62), while a shorter period (day) from early symptoms to hospitalisation reduced mortality risks (HR, 0.96;95% CI, 0.93-0.99). Conclusions: Our findings from a large international cohort of critically-ill COVID-19 patients on mechanical ventilation emphasises that elderly patients, not promptly admitted to the hospital, and who present higher creatinine levels and acidosis are at higher risk of mortality.
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Bacterial infection remains the main cause of acute respiratory distress syndrome and is a leading cause of death and disability in critically ill patients. Here we report on the use of purified ß-glucan (lentinan) extracts from Lentinus edodes (Shiitake) mushroom that can reduce infection by a multidrug-resistant clinical isolate of Klebsiella pneumoniae in a rodent pneumonia model, likely through immunomodulation. Adult male Sprague-Dawley rats were subjected to intra-tracheal administration of K. pneumoniae to induce pulmonary sepsis and randomized to three groups; vehicle control (Vehicle, n = 12), commercial lentinan (CL, n = 8) or in-house extracted lentinan (IHL, n = 8) were administered intravenously 1 h postinfection. Physiological parameters and blood gas analysis were measured, bacterial counts from bronchoalveolar-lavage (BAL) were determined, along with differential staining of white cells and measurement of protein concentration in BAL 48 h after pneumonia induction. Use of IHL extract significantly decreased BAL CFU counts. Both CL and IHL extractions reduced protein concentration in BAL. Use of IHL resulted in an improvement in physiological parameters compared to controls and CL. In conclusion, administration of lentinan to treat sepsis-induced lung injury appears safe and effective and may exert its effects in an immunomodulatory manner.